Tripeptide Leu-Pro-Phe from Corn Protein Hydrolysates Attenuates Hyperglycemia-Induced Neural Tube Defect in Chicken Embryos.

Neural tube defect (NTD) is the most common and severe embryopathy causing embryonic malformation and even death associated with gestational diabetes mellitus (GDM). Leu-Pro-Phe (LPF) is an antioxidative tripeptide isolated from hydrolysates of corn protein. However, the biological activity of LPF in vivo and in vitro remains unclear. This study is aimed at investigating the protective effects of tripeptide LPF against NTD in the high glucose exposure condition and delineate the underlying biological mechanism. We found that LPF alleviated NTD in the high glucose-exposed chicken embryo model. In addition, DF-1 chicken embryo fibroblast was loaded with high glucose for induction of oxidative stress and abnormal O-GlcNAcylation in vitro. LPF significantly decreased accumulation of reactive oxygen species and content of malondialdehyde in DF-1 cells but increased the ratio of reduced glutathione and oxidized glutathione in chick embryo. Oxygen radical absorbance capacity results showed that LPF itself had good free radical scavenging capacity and could enhance antioxidant activity of the cell content. Mechanistic studies suggested that the resistance of LPF to oxidative damage may be related to promotion of NRF2 expression and nuclear translocation. LPF alleviated the overall O-GlcNAcylation level of cellular proteins under high glucose conditions and restored the level of Pax3 protein. Collectively, our findings indicate that LPF peptide could act as a nutritional supplement for the protection of development of embryonic neural tube affected by GDM.

ALOX15-launched PUFA-phospholipids peroxidation increases the susceptibility of ferroptosis in ischemia-induced myocardial damage.

Myocardial ischemia/reperfusion (I/R) injury is a classic type of cardiovascular disease characterized by injury to cardiomyocytes leading to various forms of cell death. It is believed that irreversible myocardial damage resulted from I/R occurs due to oxidative stress evoked during the reperfusion phase. Here we demonstrate that ischemia triggers a specific redox reaction of polyunsaturated fatty acids (PUFA)-phospholipids in myocardial cells, which acts as a priming signaling that initiates the outbreak of robust oxidative damage in the reperfusion phase. Using animal and in vitro models, the crucial lipid species in I/R injury were identified to be oxidized PUFAs enriched phosphatidylethanolamines. Using multi-omics, arachidonic acid 15-lipoxygenase-1 (ALOX15) was identified as the primary mediator of ischemia-provoked phospholipid peroxidation, which was further confirmed using chemogenetic approaches. Collectively, our results reveal that ALOX15 induction in the ischemia phase acts as a "burning point" to ignite phospholipid oxidization into ferroptotic signals. This finding characterizes a novel molecular mechanism for myocardial ischemia injury and offers a potential therapeutic target for early intervention of I/R injury.